The recognition that a pool of cardiac stem cells (CSCs) is present in the adult myocardium poses the question whether CSCs are responsible for cardiomyogenesis in the embryonic, fetal and postnatal heart, regulate myocyte renewal in the adult organ and condition myocardial aging. Stem cell renewal occurs by symmetric division, which generates two daughter stem cells, or by asymmetric division, which generates one daughter cell that is identical to the mother cell and a second daughter cell which has a separate fate. This notion of stem cell growth has recently been perturbed by the resurrection of an old theory, suggesting that stem cells are capable of cosegregating the old original template DNA strands in consecutive divisions so that the daughter cell that inherits the old DNA retains stem cell features while the daughter cell that acquires the new DNA enters the transit amplifying pool. If this hypothesis is correct, the number of mother stem cells may be genetically determined sometime early in life and cannot be expanded thereafter. Conversely, this class of true stem cells may decrease dramatically as a function of age and loss of CSCs may be a critical determinant of the development of the aging myopathy. Protection of the old DNA during stem cell division cannot prevent the consequences of oxidative stress and environmental factors commonly present with the course of life and myocardial aging, independently from disease processes. Excessive growth demands on CSCs may lead to their depletion and, as a consequence, to accumulation of senescent, poorly contracting, hypertrophied cardiomyocytes. Conversely, preservation of the pool of CSCs carrying the mother DNA may delay the manifestations of the senescent cardiac phenotype. Thus, the long-term objective of this application is to establish the role of endogenous CSCs in the development of the heart prenatally and postnatally, and their function in the fully mature organ and in the initiation and progression of the aging myopathy. PUBLIC HEALTH RELEVANCE: This research is directed to the documentation whether the entire lifespan of the heart from embryonic, fetal and postnatal development to adulthood and aging is regulated by the growth and differentiation of resident cardiac stem cells. Additionally, the possibility is raised that the loss of a pool of true stem cells that is genetically determined may condition myocardial aging and heart failure.